Altretamine induces ferroptosis in small cell lung cancer by promoting epigenetic silencing and lysosomal degradation of GPX4
Menée à l'aide de lignées cellulaires et de modèles murins de cancer du poumon à petites cellules, cette étude met en évidence un mécanisme par lequel l'altrétamine induit la ferroptose des cellules cancéreuses en réprimant d'une part, l'expression du gène de la glutathion peroxydase GPX4 via la méthylation du promoteur par la méthyltransférase DNMT3A et en favorisant d'autre part, la dégradation lysosomale de GPX4 via la protéine de choc thermique constitutive HSC70
Background : Small cell lung cancer (SCLC) is a high-grade and aggressive neuroendocrine carcinoma that remains incurable due to the emergence of drug resistance and frequent relapse. This study aimed to clarify the therapeutic potential and detailed mechanism of altretamine against SCLC.
Methods : Altretamine-triggered cytotoxicity and lipid peroxidation were determined by EdU, FerroOrange probes, etc. GPX4 promoter methylation was evaluated by Methylation-specific PCR, chromatin immunoprecipitation, etc. Altretamine-induced GPX4 degradation was examined by bio-layer interferometry, immunoprecipitation, etc.
Results : Altretamine mainly initiates ferroptosis in SCLC cells, accompanied by accumulation of intracellular ROS and lipid peroxidation. Mechanistically, altretamine facilitated the binding of DNMT3A to GPX4 promoter, leading to DNA methylation of GPX4 gene and subsequent transcriptional repression. Moreover, altretamine directly bound to GPX4 protein and accelerated the lysosomal degradation of GPX4 protein in a HSC70-dependent manner. Inhibition of DNA demethylation by inactivating Ten-eleven translocation (TET) proteins synergistically strengthened the anti-SCLC activity of altretamine.
Conclusions : Our findings revealed the first time that altretamine induced ferroptotic cell death by promoting DNMT3A-mediated epigenetic silencing of GPX4 gene and HSC70-mediated lysosomal degradation of GPX4 protein in SCLC cells. Altretamine alone or in combination with TET inhibitors is a valuable and credible strategy for the clinical treatment of SCLC.
British Journal of Cancer , article en libre accès, 2026